STAT3 Inhibitor ODZ10117 Suppresses Glioblastoma Malignancy and Prolongs Survival in a Glioblastoma Xenograft Model.

Constitutively activated STAT3 plays an essential role in the initiation, progression, maintenance, malignancy, and drug resistance of cancer, including glioblastoma, suggesting that STAT3 is a potential therapeutic target for cancer therapy. We recently identified ODZ10117 as a small molecule inhibitor of STAT3 and suggested that it may have an effective therapeutic utility for the STAT3-targeted cancer therapy. Here, we demonstrated the therapeutic efficacy of ODZ10117 in glioblastoma by targeting STAT3. ODZ10117 inhibited migration and invasion and induced apoptotic cell death by targeting STAT3 in glioblastoma cells and patient-derived primary glioblastoma cells. In addition, ODZ10117 suppressed stem cell properties in glioma stem cells (GSCs). Finally, the administration of ODZ10117 showed significant therapeutic efficacy in mouse xenograft models of GSCs and glioblastoma cells. Collectively, ODZ10117 is a promising therapeutic candidate for glioblastoma by targeting STAT3.

A Visual Analytics System for Exploring, Monitoring, and Forecasting Road Traffic Congestion.

We present an interactive visual analytics system that enables traffic congestion exploration, surveillance, and forecasting based on vehicle detector data. Through domain expert collaboration, we have extracted task requirements, incorporated the Long Short-Term Memory (LSTM) model for congestion forecasting, and designed a weighting method for detecting the causes of congestion and congestion propagation directions. Our visual analytics system is designed to enable users to explore congestion causes, directions, and severity. Congestion conditions of a city are visualized using a Volume-Speed Rivers (VSRivers) visualization that simultaneously presents traffic volumes and speeds. To evaluate our system, we report performance comparison results, wherein our model is more accurate than other forecasting algorithms. We demonstrate the usefulness of our system in the traffic management and congestion broadcasting domains through three case studies and domain expert feedback.

Development of Oxadiazole-Based ODZ10117 as a Small-Molecule Inhibitor of STAT3 for Targeted Cancer Therapy.

Persistently activated STAT3 is a promising target for a new class of anticancer drug development and cancer therapy, as it is associated with tumor initiation, progression, malignancy, drug resistance, cancer stem cell properties, and recurrence. Here, we discovered 3-(2,4-dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole (ODZ10117) as a small-molecule inhibitor of STAT3 to be used in STAT3-targeted cancer therapy. ODZ10117 targeted the SH2 domain of STAT3 regardless of other STAT family proteins and upstream regulators of STAT3, leading to inhibition of the tyrosine phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3. The inhibitory effect of ODZ10117 on STAT3 was stronger than the known STAT3 inhibitors such as S3I-201, STA-21, and nifuroxazide. ODZ10117 suppressed the migration and invasion, induced apoptosis, reduced tumor growth and lung metastasis, and extended the survival rate in both in vitro and in vivo models of breast cancer. Overall, we demonstrated that ODZ10117 is a novel STAT3 inhibitor and may be a promising agent for the development of anticancer drugs.

Optimal design of a simulated-moving-bed chromatographic process for high-purity separation of acetoin from 2,3-butanediol in a continuous mode.

For the high-purity production of acetoin or 2,3-butanediol (BD) from related fermentation processes, it is essential to accomplish a detailed separation between acetoin and BD in an economical mode. To address this issue, we aimed to develop a highly-efficient simulated-moving-bed (SMB) process for the continuous-mode separation of acetoin from BD with high purity and small loss. As a first step for this task, the adsorption and mass-transfer parameters of acetoin and BD on a proven adsorbent were estimated while assuming that BD isomers (meso-BD and DL-BD) would be identical in adsorption and mass-transfer behaviors. The resultant parameters from such estimation were applied to the optimal design of the acetoin-BD separation SMB. The designed SMB was then experimentally investigated, which revealed that some sign of BD isomerism occurred in the SMB column-profile data and thus had an adverse effect on the SMB separation performance. To resolve this problem, the individual parameters of BD isomers were determined on the basis of the SMB column-profile data and an inverse-method principle. The resulting parameters of BD isomers were used in the re-design of the target SMB, which was then experimentally checked for its separation performance. It was confirmed that such SMB re-designed in consideration of BD isomerism was quite effective in the continuous-mode separation of acetoin from BD with high purity (> 99.2%) and small loss (< 1.52%).

Continuous-mode separation of fucose and 2,3-butanediol using a three-zone simulated moving bed process and its performance improvement by using partial extract-collection, partial extract-recycle, and partial desorbent-port closing.

If a multi-component monosugar mixture including fucose was used as the substrates for the Klebsiella oxytoca fermentation, it could offer the following two benefits simultaneously; (i) the removal of all monosugars other than fucose, and (ii) the acquisition of 2,3-butanediol (BD). To utilize such two benefits in favor of the economical efficiency of the fucose production process, it is essential to accomplish a high-purity separation between fucose and BD on the basis of a highly-economical mode. To address this issue, we aimed to develop a simulated moving bed (SMB) process for continuous-mode separation of fucose and BD with high purities. It was first found that an Amberchrom-CG71C resin could become a suitable adsorbent for the separation of interest. The intrinsic parameters of fucose and BD on such proven adsorbent were determined, and then applied to the optimal design of the fucose-BD separation SMB. The capability of the designed SMB in ensuring high purities and high yields was experimentally verified. Finally, we devised two potential strategies to make a further improvement in product concentrations and/or desorbent usage while keeping the purities and yields of fucose and BD almost unchanged. The first strategy was based on partial extract-collection and partial extract-discard, which was found to result in 33% higher BD product concentration. The second strategy was based on partial extract-collection, partial extract-recycle, and partial desorbent-port closing, which could lead to 25% lower desorbent usage, 33% higher BD product concentration, and 7% higher fucose product concentration.

Standing wave design and optimization of a simulated moving bed chromatography for separation of xylobiose and xylose under the constraints on product concentration and pressure drop.

The feasibility of a simulated moving bed (SMB) technology for the continuous separation of high-purity xylobiose (X2) from the output of a ß-xylosidase X1→X2 reaction has recently been confirmed. To ensure high economical efficiency of the X2 production method based on the use of xylose (X1) as a starting material, it is essential to accomplish the comprehensive optimization of the X2-separation SMB process in such a way that its X2 productivity can be maximized while maintaining the X2 product concentration from the SMB as high as possible in consideration of a subsequent lyophilization step. To address this issue, a suitable SMB optimization tool for the aforementioned task was prepared based on standing wave design theory. The prepared tool was then used to optimize the SMB operation parameters, column configuration, total column number, adsorbent particle size, and X2 yield while meeting the constraints on X2 purity, X2 product concentration, and pressure drop. The results showed that the use of a larger particle size caused the productivity to be limited by the constraint on X2 product concentration, and a maximum productivity was attained by choosing the particle size such that the effect of the X2-concentration limiting factor could be balanced with that of pressure-drop limiting factor. If the target level of X2 product concentration was elevated, higher productivity could be achieved by decreasing particle size, raising the level of X2 yield, and increasing the column number in the zones containing the front and rear of X2 solute band.

Design of simulated moving bed for separation of fumaric acid with a little fronting phenomenon.

The production of fumaric acid through a biotechnological pathway has grown in importance because of its potential value in related industries. This has sparked an interest in developing an economically-efficient process for separation of fumaric acid (product of interest) from acetic acid (by-product). This study aimed to develop a simulated moving bed (SMB) chromatographic process for such separation in a systematic way. As a first step for this work, commercially available adsorbents were screened for their applicability to the considered separation, which revealed that an Amberchrom-CG71C resin had a sufficient potential to become an adsorbent of the targeted SMB. Using this adsorbent, the intrinsic parameters of fumaric and acetic acids were determined and then applied to optimizing the SMB process under consideration. The optimized SMB process was tested experimentally, from which the yield of fumaric-acid product was found to become lower than expected in the design. An investigation about the reason for such problem revealed that it was attributed to a fronting phenomenon occurring in the solute band of fumaric acid. To resolve this issue, the extent of the fronting was evaluated quantitatively using an experimental axial dispersion coefficient for fumaric acid, which was then considered in the design of the SMB of interest. The SMB experimental results showed that the SMB design based on the consideration of the fumaric-acid fronting could guarantee the attainment of both high purity (>99%) and high yield (>99%) for fumaric-acid product under the desorbent consumption of 2.6 and the throughput of 0.36L/L/h.

The critical roles of tumor-initiating cells and the lymph node stromal microenvironment in human colorectal cancer extranodal metastasis using a unique humanized orthotopic mouse model.

Colorectal cancer (CRC) is the second-most common cause of cancer-related mortality. The most important prognostic factors are lymph node (LN) involvement and extranodal metastasis. Our objective is to investigate the interactions between CD133(+)CXCR4(+) (CXC receptor 4) colorectal cancer tumor-initiating cells (Co-TICs) and the LN stromal microenvironment in human CRC extranodal metastasis. We established a unique humanized orthotopic xenograft model. Luciferase-tagged CRC cell lines and human cancer cells were injected intrarectally into nonobese diabetic/SCID mice. Mesenteric LN stromal cells, stromal cell line HK, or CXCL12 knockdown HK (HK-KD-A3) cells were coinoculated with CRC cells. Tumor growth and metastasis were monitored by bioluminescent imaging and immunohistochemistry. We found that this model mimics the human CRC metastatic pattern with CRC cell lines or patient specimens. Adding LN stromal cells promotes CRC tumor growth and extranodal metastasis (P < 0.001). Knocking down CXCL12 impaired HK cell support of CRC tumor formation and extranodal metastasis. When HK cells were added, sorted CD133(+)CXCR4(+) Co-TICs showed increased tumor formation and extranodal metastasis capacities compared to unseparated and non-Co-TIC populations. In conclusion, both Co-TIC and LN stromal factors play crucial roles in CRC metastasis through the CXCL12/CXCR4 axis. Blocking Co-TIC/LN-stromal interactions may lead to effective therapy to prevent extranodal metastasis.

A rare fraction of drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumourigenic potential.

Follicular lymphoma (FL) comprises nearly 25% of non-Hodgkin lymphoma cases and is clinically characterized by initial sensitivity to chemotherapy followed by relapse. FL stroma contains a special type of stromal cell found in the germinal centre of lymph nodes-the follicular dendritic cell (FDC). We first isolated tumourigenic cells from the FL cell line FLK-1 by side population (SP) technique, and found that SP cells, which express ABCG2, were enriched by chemotherapy and radiation treatments. In vitro, SP cells were attracted by and adhered to FDCs through chemokine (C-X-C motif) ligand 12/chemokine (C-X-C motif) receptor 4 (CXCL12/CXCR4) signalling. In vivo, limiting dilution assays showed SP cells were highly enriched in cancer stem cells (CSC), but required FDC for tumour formation in non-obese diabetic/severe combined immunodeficiency mice. Treatment with AMD3100, a specific CXCL12/CXCR4 inhibitor, eliminated tumour growth. These findings were then verified with FL cells isolated from an FL patient's ascitic fluid (FLA-1). Finally, we detected the ABCG2 expressing lymphoma cells in FL clinical specimens. Thus, we found that the highly tumourigenic FL cells having CSC-like activities (FL-SC) interact with FDCs in a CXCL12/CXCR4 dependent manner to resist chemotherapy. Our results indicate the importance of FL-SC and niche cell signalling in maintaining tumourigenicity. These signals represent novel targets for CSC eradication.

Transcription-coupled events associating with immunoglobulin switch region chromatin.

Class switch recombination (CSR) at the antibody immunoglobulin locus is regulated by germline transcription (GLT)-coupled modifications in the accessibility of the switch region, where CSR takes place. Here we show that histone acetylation of switch regions is linked to CSR but that histone acetylation cannot alone promote CSR or GLT. Activation-induced cytidine deaminase (AID) specifically associates with the CSR target chromatin in a GLT-coupled manner, which may occur potentially by means of physical interaction between AID and the transcription machinery. These data indicate an important role of GLT in the regulation of chromatin accessibility, strongly suggesting that the target of AID is chromatin DNA. Our results give insights on the role of AID and the regulatory mechanism of CSR.